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J. Biol. Chem., Vol. 279, Issue 18, 19276-19285, April 30, 2004

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Targeted Mutation of the MLN64 START Domain Causes Only Modest Alterations in Cellular Sterol Metabolism^*

Tatsuro Kishida, Igor Kostetskii, Zhibing Zhang, Federico Martinez, Pei Liu, Steven U. Walkley¶, Nancy K. Dwyer, E. Joan Blanchette-Mackie||, Glenn L. Radice, and Jerome F. Strauss , III**

From the Center for Research on Reproduction and Women's Health, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, the ^¶Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, and the ^||Lipid Cell Biology Section, Laboratory of Cell Biochemistry and Biology, NIDDK, National Institutes of Health, Bethesda, Maryland 20892

The StAR-related lipid transfer (START) domain, first identified in the steroidogenic acute regulatory protein (StAR), is involved in the intracellular trafficking of lipids. Sixteen mammalian START domain-containing proteins have been identified to date. StAR, a protein targeted to mitochondria, stimulates the movement of cholesterol from the outer to the inner mitochondrial membranes, where it is metabolized into pregnenolone in steroidogenic cells. MLN64, the START domain protein most closely related to StAR, is localized to late endosomes along with other proteins involved in sterol trafficking, including NPC1 and NPC2, where it has been postulated to participate in sterol distribution to intracellular membranes. To investigate the role of MLN64 in sterol metabolism, we created mice with a targeted mutation in the Mln64 START domain, expecting to find a phenotype similar to that in humans and mice lacking NPC1 or NPC2 (progressive neurodegenerative symptoms, free cholesterol accumulation in lysosomes). Unexpectedly, mice homozygous for the Mln64 mutant allele were viable, neurologically intact, and fertile. No significant alterations in plasma lipid levels, liver lipid content and distribution, and expression of genes involved in sterol metabolism were observed, except for an increase in sterol ester storage in mutant mice fed a high fat diet. Embryonic fibroblast cells transfected with the cholesterol side-chain cleavage system and primary cultures of granulosa cells from Mln64 mutant mice showed defects in sterol trafficking as reflected in reduced conversion of endogenous cholesterol to steroid hormones. These observations suggest that the Mln64 START domain is largely dispensable for sterol metabolism in mice.

Received for publication, January 22, 2004 , and in revised form, February 12, 2004.

^* This work was supported by the Ara Parseghian Medical Research Foundation and National Institutes of Health (NIH) Grant HD06274. Assays of glucose and free fatty acid levels and transmission electron microscopy were performed by core facilities of the University of Pennsylvania Diabetes and Endocrinology Center, supported by NIH Grant P30 DK 19525. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by NIH Grant DW43 TW00671.

^** To whom correspondence should be addressed: Center for Research on Reproduction and Women's Health, 1354 BRB, 421 Curie Blvd., Philadelphia, PA 19104. Tel.: 215-898-0147; Fax: 215-573-5408; E-mail: jfs3{at}mail.med.upenn.edu.

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